Protein accumulations do important work in the human body, but something can go wrong and proliferate in those aggregates, resulting in neurodegeneration and diseases such as Parkinson's and Alzheimer's.
One such assembly, amyloid beta peptide, is synonymous with dementia, but researchers were not certain how these peptide assemblies "break bad" and what really causes them to assemble.
Now, researchers at Washington University in St. Louis have found a critical role for the physical interfaces of these amyloid beta peptides in determining the chemical dynamics of their assemblies. This is crucial to understanding how to develop therapies that can disrupt toxic pathways that lead to Alzheimer's or ALS.
Think of these protein accumulations as structural scaffolding that generates "holes" and "nails" itself.
Previous understanding of amyloid aggregation was that it goes through a series of physical changes that determine how it functions. But Yifan Dai, an assistant professor of biomedical engineering in the McKelvey School of Engineering at WashU, instead found the structure's function is also encoded in its "interfacial electrical field," the surface that modulates the chemical activities of other molecules.
In research published in the Journal of the American Chemical Society, Dai's group and colleagues from Stanford and Columbia universities show that these surfaces can form an electric field that oxidizes water molecules to generate "highly reactive oxygen species" that send the peptide down a toxic path.
Reactive oxygen molecules add stress on the cell and DNA that turns that nanoscale scaffolding rotten. Through that electric field, amyloid beta peptides establish a positive feedback loop that accelerates production and aggregation of fibrils (a key link in the expansion of that nanoscale scaffolding).
"The beta amyloid monomer itself is chemically inert, but higher order assembly of these monomers becomes toxic," Dai said. This raised researchers' interest in how biological matter with distinct length scale can encode different functions through the generation of a distinct stable surface, he added.
Previously, researchers thought the highly reactive forms of molecular oxygen emerge from enzymatic pathways.
But with the current research, Dai saw that the electrical field itself can stretch the bond of the molecules similar to how an enzyme works, and once that bond is stretched, the energy differential produces reactive oxygen species that turn the scene toxic.
The big takeaway for biomedical researchers is that amyloid aggregation includes not only a physical process but a chemical "crosslinking" as well - a process researchers can potentially disrupt.
"This is where the toxicity comes from, directly from the assembly of amyloid during the phase transitions," said Michael W. Chen, a graduate student at McKelvey Engineering. Chen and postdoctoral scholar Xiaokang Ren are co-lead authors with Dai.
They also identified small molecules capable of breaking the chemical feedback loop that drives that toxicity. These compounds work by scavenging hydroxyl radicals - a type of reactive oxygen molecules - or perturbing the interface.
Such molecules are widely available in foods that have antioxidant properties, providing further evidence that proper nutrition can factor into protecting against dementia.
"Drinking more coffee and eating more berries and nuts might help detoxify this process," Dai said.
Chen MW, Ren X, Song X, Qian N, Ma Y, Yu W, Yang L, Min W, Zare RN, Dai Y. Transition state-dependent spontaneous generation of reactive oxygen species by Aβ assemblies encodes a self-regulated positive feedback loop for aggregate formation. Journal of the American Chemical Society Feb. 25.
